title: Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis.
abstract: The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controversial. We have generated humanized mice expressing the multiple sclerosis-associated MHC class I alleles HLA-A(*)0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A(*)0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8(+) T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3-restricted CD8(+) T cells in induction of multiple sclerosis-like disease and for CD4(+) T cells in its progression, and we also define a possible mechanism for HLA-A(*)0201-mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8(+) T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford, UK.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
authors.forename: Karen B
authors.initials: KB
authors.lastname: Jakobsen
authors.forename: Lone
authors.initials: L
authors.lastname: Friis
authors.forename: Ruth
authors.initials: R
authors.lastname: Etzensperger
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Craner
authors.forename: Róisín M
authors.initials: RM
authors.lastname: McMahon
authors.forename: Lise T
authors.initials: LT
authors.lastname: Jensen
authors.forename: Véronique
authors.initials: V
authors.lastname: Huygelen
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: John I
authors.initials: JI
authors.lastname: Bell
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell